Maraviroc

Maraviroc is a potent and selective antagonist of Chemokine Receptor CCR5 [1].

CCR5 is a receptor for chemokines and exists on the surface of white blood cells that are involved in the immune system. Many forms of HIV enter and infect host cells through CCR5 [1].

Maraviroc is a potent and selective inhibitor of CCR5 with potent anti-HIV-1 activity. Maraviroc exhibited antiviral activity against all CCR5-tropic HIV-1 viruses tested with IC90 of 2.0 nM. In HeLa P4 cells, maraviroc inhibited binding of viral envelope gp120 to CCR5 with IC50 value of 11 nM and prevented the membrane fusion events, which were necessary for viral entry. While, maraviroc didn’t affect CCR5 levels or associated intracellular signaling, which suggested it is an antagonist of CCR5 [1].

In a patient infected with both R5-tropic and X4-tropic HIV-1 viruses, treatment with maraviroc suppressed all R5-tropic viruses. And the R5-tropic viruses were replaced by more X4-tropic viruses [2].

References:
[1].  Dorr P, Westby M, Dobbs S, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother, 2005, 49(11): 4721-4732.
[2].  Symons J, van Lelyveld SF, Hoepelman AI, et al. Maraviroc is able to inhibit dual-R5 viruses in a dual/mixed HIV-1-infected patient. J Antimicrob Chemother, 2011, 66(4): 890-895.

Randomized controlled trial of the tolerability and completion of maraviroc compared with Kaletra(R) in combination with Truvada(R) for HIV post-exposure prophylaxis (MiPEP Trial).[Pubmed:28369381]

J Antimicrob Chemother. 2017 Jun 1;72(6):1760-1768.

Objectives: Post-exposure prophylaxis (PEP) for HIV is often poorly tolerated and not completed. Alternative PEP regimens may improve adherence and completion, aiding HIV prevention. We conducted a randomized controlled trial of a Maraviroc-based PEP regimen compared with a standard-of-care regimen using ritonavir-boosted lopinavir. Methods: Patients meeting criteria for PEP were randomized to tenofovir disoproxil/emtricitabine (200/245 mg) once daily plus ritonavir-boosted lopinavir (Kaletra (R) 400/100 mg) or Maraviroc 300 mg twice daily. The composite primary endpoint was completion of 28 days of the allocated PEP regimen without grade 3 or 4 clinical or laboratory adverse events (AEs) related to the PEP medication. Results: Two hundred and thirteen individuals were randomized (107 to Maraviroc; 106 to Kaletra (R) arm). Follow-up rates were high in both groups. There was no difference in the primary endpoint; 70 (71%) in the Maraviroc and 64 (65%) in the Kaletra (R) arm ( P = 0.36) completed PEP without grade 3 or 4 AEs. Discontinuation of PEP was the same (18%) in both groups. There were no grade 3 or 4 clinical AEs in either arm, but more grade 1 or 2 clinical AEs in the Kaletra (R) arm (91% versus 70%; P < 0.001). Antidiarrhoeal medication use was higher in the Kaletra (R) arm (67% versus 25%; P < 0.001). There were no HIV seroconversions in the study period. Conclusions: The completion rate in the absence of grade 3 or 4 AEs was similar with both regimens. Maraviroc-based PEP was better tolerated, supporting its use as an option for non-occupational PEP.

Maraviroc reduces neuropathic pain through polarization of microglia and astroglia - Evidence from in vivo and in vitro studies.[Pubmed:27117708]

Neuropharmacology. 2016 Sep;108:207-19.

Recent studies suggest that CCR5 and its ligands are important regulators for the development of neuropathic pain and that their modulation can have some beneficial properties. Therefore, the aim of our study was to investigate the influence of Maraviroc (MVC, a CCR5 antagonist) on glial polarization markers and intracellular signaling pathways in the spinal cord 7 days after chronic constriction injury (CCI) to the sciatic nerve and in primary glial cultures after LPS stimulation. Our results demonstrated that chronic intrathecal administration of MVC diminished neuropathic pain symptoms and nociceptive threshold approximately 60 min after drug administration on days 3 and 7 post-CCI. MVC downregulated the levels of phosphorylated p38 MAPK, ERK1/2 and NF-kappaB proteins in the spinal cord and upregulated STAT3 in the dorsal root ganglia (DRG). Additionally, using Western blot analysis, we demonstrated that MVC effectively diminished "classical" activation markers: IL-1beta, IL-18, IL-6 and NOS2 in the spinal cord. In contrast, MVC upregulated "alternative" antinociceptive activation markers: IL-1RA, IL-18BP and IL-10 in the spinal cord. In parallel, MVC downregulated the levels of phosphorylated p38 MAPK, ERK1/2 and NF-kappaB proteins and upregulated STAT3 in microglial and astroglial cell cultures. Similarly, MVC reduced pronociceptive (IL-1beta, IL-18, IL-6, NOS2) and enhanced the antinociceptive (IL-1RA, IL-18BP, IL-10) factors after LPS stimulation. Our studies provide new evidence that MVC attenuates neuropathy symptoms, promotes spinal glial "alternative" polarization and restores the balance between pro- and antinociceptive factors. Our results suggest the modulation of CCR5 by MVC as a novel therapeutic approach for neuropathy.

New insights into the mechanisms whereby low molecular weight CCR5 ligands inhibit HIV-1 infection.[Pubmed:21118814]

J Biol Chem. 2011 Feb 18;286(7):4978-90.

CC chemokine receptor 5 (CCR5) is a G-protein-coupled receptor for the chemokines CCL3, -4, and -5 and a coreceptor for entry of R5-tropic strains of human immunodeficiency virus type 1 (HIV-1) into CD4(+) T-cells. We investigated the mechanisms whereby nonpeptidic, low molecular weight CCR5 ligands block HIV-1 entry and infection. Displacement binding assays and dissociation kinetics demonstrated that two of these molecules, i.e. TAK779 and Maraviroc (MVC), inhibit CCL3 and the HIV-1 envelope glycoprotein gp120 binding to CCR5 by a noncompetitive and allosteric mechanism, supporting the view that they bind to regions of CCR5 distinct from the gp120- and CCL3-binding sites. We observed that TAK779 and MVC are full and weak inverse agonists for CCR5, respectively, indicating that they stabilize distinct CCR5 conformations with impaired abilities to activate G-proteins. Dissociation of [(125)I]CCL3 from CCR5 was accelerated by TAK779, to a lesser extent by MVC, and by GTP analogs, suggesting that inverse agonism contributes to allosteric inhibition of the chemokine binding to CCR5. TAK779 and MVC also promote dissociation of [(35)S]gp120 from CCR5 with an efficiency that correlates with their ability to act as inverse agonists. Displacement experiments revealed that affinities of MVC and TAK779 for the [(35)S]gp120-binding receptors are in the same range (IC(50) approximately 6.4 versus 22 nm), although we found that MVC is 100-fold more potent than TAK779 for inhibiting HIV infection. This suggests that allosteric CCR5 inhibitors not only act by blocking gp120 binding but also alter distinct steps of CCR5 usage in the course of HIV infection.

Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity.[Pubmed:16251317]

Antimicrob Agents Chemother. 2005 Nov;49(11):4721-32.

Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin (geometric mean 90% inhibitory concentration of 2.0 nM). Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. There was little difference in the sensitivity of the 200 viruses to Maraviroc, as illustrated by the biological cutoff in this assay (= geometric mean plus two standard deviations [SD] of 1.7-fold). The mechanism of action of Maraviroc was established using cell-based assays, where it blocked binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry. Maraviroc did not affect CCR5 cell surface levels or associated intracellular signaling, confirming it as a functional antagonist of CCR5. Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel (50% inhibitory concentration, >10 microM), indicating potential for an excellent clinical safety profile. Studies in preclinical in vitro and in vivo models predicted Maraviroc to have human pharmacokinetics consistent with once- or twice-daily dosing following oral administration. Clinical trials are ongoing to further investigate the potential of using Maraviroc for the treatment of HIV-1 infection and AIDS.